Asthma—A Heterogeneous Disease
Asthma is a chronic inflammatory disorder of the airways characterized by marked variability in airflow obstruction that is often reversible, either spontaneously or with treatment.1 This inflammation presents clinically in susceptible patients with recurrent symptoms of wheezing, chest tightness, cough, and, occasionally, dyspnea and contributes to the heightened airway hyperresponsiveness to specific and nonspecific stimuli; a pathognomonic feature of asthma. Increased airway hyperresponsiveness manifests in patients as intolerance to smoke, dust, air pollution, and strong odors, where exposure to such agents in healthy individuals does not induce such symptoms. Asthma is not a single disease entity with a unique pathogenesis, but rather recognized to be a clinical syndrome and heterogeneous disease;2 that is, asthma comprises multiple endotypes that manifest common symptoms, but have distinct and probably different pathophysiologic and etiologic mechanisms with an interplay between genetic and environmental factors. This phenotypic heterogeneity in the expression of asthma is multidimensional and includes variability in pathologic, clinical, and physiologic parameters among different patients.3 Recent attention has directed focus on traits that are identifiable and treatable in patients with asthma, such as persistently elevated blood eosinophils, in order to achieve precision treatment with the hope of better patient outcomes.4
Several risk factors for asthma are considered below.
The most important factor predisposing to asthma is atopy (Table 46-1). Asthma has been classified as atopic (extrinsic) or nonatopic (intrinsic) depending on the suspected role of allergens as etiologic factors. Atopic asthma involves an exaggerated immune response characterized by immunoglobulin E (Ig-E) activation and mast cell degradation. Atopy can be clinically elicited with a positive skin prick test or specific antibodies to IgE in serum against common aeroallergens such as house dust mite, grass and tree pollens, cat and dog fur, rodents (in laboratory workers), and cockroaches (in inner city populations). House dust mite is recognized as a significant cause of asthma throughout the developed world, although the relative importance of different indoor allergens may vary among populations. Patients with atopic asthma commonly suffer from other atopic diseases, including allergic rhinitis that may be seasonal (hayfever), and may be found in over 80% of asthmatic patients; allergic conjunctivitis; and atopic dermatitis (eczema). Nonatopic asthmatic patients (approximately 10%) have a negative skin prick test, normal serum IgE concentrations, and usually show later onset of disease (adult-onset asthma). In this group, their asthma is more severe, persistent, there is more sensitivity to aspirin and commonly they have concomitant nasal polyps. This classification, although appropriate from a pathologic perspective, does not readily help clinicians as it does not aid in establishing an etiologic diagnosis nor does it help in defining treatment strategies.5 There is a high prevalence of atopy among non-asthmatics and a large percentage of skin prick sensitive persons report no allergic symptoms. Around 50% of asthma can be attributed to atopy in the developed world and the prevalence of atopy among asthmatics is mainly determined by the general prevalence of atopy in the population.6,7 In addition, the immunopathology in bronchial biopsies and sputum in patients with nonatopic asthma appear to be identical to that found in atopic asthmatic patients. Therefore, the finding that an asthmatic is atopic does not imply that the disease is allergic in nature or, that atopy is causing asthma. Moreover, respiratory tract viruses have emerged as the most frequent triggers for exacerbations in both children and adults and may play a more prominent role than allergens as triggers of acute exacerbations in most patients.8 House dust mites are the most common indoor allergen, where particles excreted from the digestive tract contain the principal allergen Dermatophagoides pteronyssinus. Other main sources of inhaled indoor allergen are cat and dog fur, and cockroaches (Table 46-1). Although asthmatic symptoms often improve when the allergen is removed, rigorous allergen avoidance has not shown any evidence for a reduced risk of developing asthma.
Table 46-1Risk Factors and Triggers Involved in Asthma ||Download (.pdf) Table 46-1 Risk Factors and Triggers Involved in Asthma
|Endogenous Factors ||Environmental Factors ||Triggers |
|Atopy ||Allergens–indoor ||Allergens (especially house dust mite, animal dander, cockroach, indoor fungi, perennial allergens, and seasonal pollens) |
|Airway hyperresponsiveness ||Allergens–outdoor (fungi, pollens) ||Changes in the weather (cold air, thunderstorms) |
|Ethnicity ||Obesity ||Drugs (angiotensin-converting enzyme inhibitors, aspirin, ?-blockers, NSAIDs) |
|Gender ||Occupational sensitizers ||Exercise and hyperventilation |
|Genetic predisposition ||Parasitic infections ||Extreme emotional expression (laughing, stress) |
| ||Respiratory infections (early childhood, viral) ||Irritants (household sprays, paint fumes) |
| ||Socioeconomic status ||Respiratory infections |
| ||Tobacco smoking (active and passive) ||Sulfur dioxide and pollutant gases |
Although allergens are often triggers of acute exacerbations of asthma, allergens themselves may induce subclinical airway inflammation that may lead to enhanced airway responsiveness and greater susceptibility to the provocative effects of other triggers such as respiratory viral infections and exercise. In this regard, it is important to understand the distinction between triggers and etiologic risk factors. A trigger is any agent capable of inducing or exacerbating asthma and whereas triggers may lead to symptoms, they do so only in susceptible persons who already possess the underlying asthmatic diathesis.
Acute upper respiratory tract viral infections are the commonest triggers of exacerbations of asthma and most are due to rhinovirus infections. Viral infections not only give symptoms of the common cold and cause acute inflammatory rhinitis, but may also play a role in asthma development and potentially, airway remodeling through increasing inflammation in the lower airways.9 Asthma is recognized to be more common in children who have had croup or lower respiratory tract infections in early life, although viral infections in the absence of atopy do not appear to be risk factors for the development of asthma.10 Other viruses commonly implicated in acute exacerbations of asthma are respiratory syncytial virus, influenza virus, and parainfluenza virus. Bacterial infection with species of Mycoplasma and Chlamydia are also associated with exacerbations of asthma, whereas other bacterial infections are not.
Occupational asthma accounts for approximately 5% of all adult cases of asthma, and the disease can often be classified according to its etiology. In these circumstances, not only is the specific agent that triggers the symptoms known, but the same agent is usually the underlying cause of asthma.
Many asthma patients have worsening of symptoms on or after physical exercise and another category of asthma is exercise-induced, where exercise per se is not the cause of, but rather one of many nonimmunologic triggers that produce symptoms in patients who already have the disease. In this condition, the trigger is thought to be the drying of the airway mucosa as a result of hyperventilation that leads to osmotically induced mast cell mediator release and bronchospasm.11
Obesity is a major risk factor for asthma where abdominal obesity (waist circumference) and general obesity (BMI) both show a strong correlation with the risk of new-onset asthma.12 Obese asthmatics often have excessive symptoms and are less responsive to corticosteroid therapy.
Drugs that may worsen asthma control include β-blockers, occasionally angiotensin-converting enzyme (ACE) inhibitors, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs).
Although not a risk factor in the true sense, it is increasingly being recognised that untreated small airways inflammation disease may predispose patients to worsening asthma, and studies show that the prevalence of small airways disease is approximately 50% in the asthmatic population.13,14
Clinical Presentation and Diagnosis
Asthma is a clinical diagnosis made on the basis of a medical history of typical symptoms, consideration to provocative factors, and supported with objective confirmation of variable airflow obstruction. As the disease is heterogeneous in its presentation and severity, the clinical features of asthma show great variability both between individual asthmatics, and also within the same patient over time. It is also important to recognize that asthma is often associated with different comorbidities including allergic rhinitis, atopic dermatitis, rhinosinusitis, gastroesophageal reflux disease, diabetes, depression, obesity, all of which may affect the clinical expression and severity of the disease.15 The following clinical features and laboratory assessments are important in the consideration of the diagnosis of asthma.
The typical symptoms of asthma are paroxysmal wheezing, cough, breathlessness, and chest tightness, which may temporally be related to exposure to triggers or exercise. Cough may be productive of clear or yellow/green discolored sputum, where the latter may be tenacious and difficult to expectorate and reflect the underlying airway inflammation rather than a respiratory infection. Indeed, cough may be present in isolation to other symptoms and as the sole manifestation of an episode of asthma.16 Breathlessness may occur as a result of the dynamic lung hyperinflation that accompanies acute asthma episodes and patients may report the sensation of difficulty in “getting air in” their lungs. Exertional symptoms may not be apparent if the patient's ability to exert themselves is limited by other health conditions such as rheumatologic or cardiac disease and, therefore, asthma may be underdiagnosed in the elderly. No single symptom is specific or more significant for asthma, although wheezing is a useful sign, as non-asthmatics rarely report frequent wheezing. In younger patients, the symptom of chest tightness is helpful, since it occurs more often in association with asthma than with other pulmonary or cardiac disorders. The pattern of symptom occurrence, the precipitating or aggravating factors, and the profile of a typical exacerbation are important elements in the clinical evaluation.
In patients with poorly controlled asthma, symptoms may temporally evolve slowly over days or weeks, or present abruptly. The severity and frequency with which symptoms occur varies greatly within the asthmatic population. The recurrent paroxysmal nature of symptom presentation is characteristic of asthma and symptoms improve, sometimes rather spontaneously, although usually with treatment. Nocturnal episodes are common in adult asthmatics and typically patients awake in the early hours of the morning with symptoms. Distinguishing whether nocturnal symptoms are due to asthma, angina, or gastroesophageal reflux may be difficult, but early-morning asthma symptoms are usually relieved with administration of inhaled bronchodilators, in contrast to cardiovascular symptoms which occur at any time during the night and, gastroesophageal reflux which tends to usually cause symptoms soon after the patient reclines at night.
Chest symptoms that vary by season and are accompanied by symptoms of irritation of other mucus membranes, such as conjunctivitis and rhinitis, are typical of allergic asthma. Triggers such as indoor allergens of house dust mite, cockroach, and animal dander proteins are more likely to result in perennial symptoms, whereas pollens and some mold spores are likely to provoke seasonal symptoms. The presence of rhinosinusitis, nasal polyps, conjunctivitis, or eczema, coupled with a family history of asthma or atopy, may further support the diagnosis of asthma. Symptoms after heavy exertion, especially in the cold air, are highly suggestive of exercise-induced asthma and typically, patients experience symptoms at the end of exercise, rather than during its performance. Excessive coughing after exercise in the absence of wheeze may also be a sign of asthma. Premenopausal women with asthma may experience a deterioration of asthma control perimenstrually.17 The medical history should elicit risk factors for asthma (Table 46-1), and special consideration should address symptoms induced by aspirin or those associated with the patient's occupation.
Asthma and Aspirin Sensitivity
The association of asthma and sensitivity to aspirin or other NSAIDs is well established.18 Aspirin-sensitive asthma affects approximately 1-5% of all asthmatics, although it is more common in patients with severe asthma (∼20%), in some ethnic groups (such as Eastern Europeans and Japanese) and in those frequently hospitalized for their asthma. This subtype of asthma is usually characterized by a tetrad of asthma, nasal polyps, chronic hypertrophic eosinophilic sinusitis, and aspirin intolerance. Classically, perennial rhinitis is the first symptom in this syndrome, preceding the development of aspirin sensitivity, and then followed much later by nasal polyps that are usually bilateral and originate from the turbinates and the paranasal sinuses. Even in small doses, aspirin typically causes wheezing, facial flushing, rhinorrhea, and conjunctival irritation. Although aspirin-induced asthmatic episodes often resemble allergic reactions, there is no evidence that immunolglobulin (Ig)-E–related mechanisms are at work. Aspirin-induced asthma is due to blockade of cyclooxygenase 1 by nonsteroidal anti-inflammatory drugs and has been associated with enhanced leukotriene production and mast cell activation, but the cellular pathways responsible for these events remain unclear. The diagnosis of aspirin sensitivity is made on the basis of the clinical history and can be confirmed by a provocative aspirin challenge, although this test carries a potential health risk of anaphylaxis for the patient.
Aspirin-sensitive asthma usually responds to standard therapy with inhaled corticosteroids (ICSs), although the condition is associated with severe asthma, who are a group of patients often refractory to treatment with inhaled and oral CS. Potentially, anti-leukotriene therapy should be efficacious in these patients, but have been found to be no more effective compared to their use in patients with allergic asthma. Aspirin desensitization may sometimes be needed, and should only be performed in specialized centers. In all asthmatic patients with aspirin sensitivity, the nonselective cyclooxygenase (COX) inhibitors should be avoided, but when an anti-inflammatory analgesic is needed, the selective COX-2 inhibitors are usually safe to use.
Occupational asthma is asthma arising de novo that is initiated as a consequence of exposure to a specific etiologic agent in people without prior asthma. In contrast, work-exacerbated asthma is defined as the worsening of asthma, that is already pre-existing or concurrent, triggered by non-specific irritants in the workplace.19 Occupational asthma may be classified into (i) that caused by a sensitizing agent in the workplace (sensitizer-induced asthma) where the specific sensitizing agent causes asthma through an identified underlying immunologic mechanism and (ii) asthma caused by exposure to irritant compounds (irritant-induced asthma) where the exposure agent is not considered to be sensitizing.20 Table 46-2 highlights the causes of both sensitizer-induced occupational asthma and the common agents responsible for irritant-induced occupational asthma. The diagnosis of occupational asthma is based on a demonstrable link between asthma symptoms and workplace exposure, showing work-related variability in measurements of lung function made serially.20 Classically, a typical history of asthma-like symptoms during the working week and improvement over the weekend or on vacation are elicited and symptoms may occur either during exposure to the etiologic substance, or they may be delayed until the evening or night after the work day. Early detection and avoidance of occupational asthma is important where, if the patient is removed from exposure within the first 6 months of symptoms, there is usually complete recovery.
Table 46-2Causes of Occupational Asthma ||Download (.pdf) Table 46-2 Causes of Occupational Asthma
|Sensitizing Agent-Induced Asthma |
|Agent ||Workers at Risk |
|Acrylate ||Dental workers; adhesive handlers |
|Anhydrides ||Workers using epoxy resin for plastics |
|Animal protein allergens ||Veterinary workers; animal handlers |
|Cereals (grains) ||Bakery workers; grain workers; farmers |
|Dyes ||Textile workers |
|Enzymes ||Pharmaceutical workers; bakery workers; laboratory workers |
|Formaldehyde, glutaraldehyde ||Hospital and healthcare workers |
|Gums ||Carpet makers |
|Isocyanates ||Installers of insulation; manufacturers of plastics; rubbers and foam; spray painters |
|Latex ||Healthcare workers; rubber workers |
|Persulfate ||Hairdressers |
|Seafoods ||Seafood handlers and processors |
|Wood dusts ||Forestry workers; sawmill workers; carpenters |
| Common Agents Responsible for Irritant-Induced Asthma |
|Acids (acetic, hydrochloric, sulfuric) || |
|Alkaline dust || |
|Ammonia || |
|Bleach || |
|Chlorine || |
|Cleaning agents || |
|Diesel exhaust || |
|Endotoxins || |
|Formalin || |
|Mustard || |
|Oxide (calcium) || |
|Paints (heated) || |
The most typical physical finding in asthma is wheezing on auscultation, which is usually caused by turbulent airflow through narrowed airways. Wheezing may be heard throughout the chest and is classically polyphonic, present to a greater extent during expiration, although it may also be heard during inspiration. The quality and character of wheezing is not specific to asthma or to the severity of the underlying disease. There may be no abnormal physical findings when asthma is under control yet conversely, in cases of very severe airway obstruction, breath sounds and wheezing may be absent. Examination of the upper respiratory tract may reveal clinical signs of rhinitis, sinusitis, or nasal polyps.
During an acute exacerbation of disease, physical signs of increased ventilation may be observed with the use of accessory muscles of respiration and chest signs of hyperinflation. A sign of severe airway obstruction is pulsus paradoxus, which is the exaggerated decrease in systolic blood pressure during inspiration by >10 mm Hg. As ventilatory effort can be diminished with respiratory muscle fatigue, pulsus paradoxus may be absent, but its absence does not preclude severe airway obstruction. Stridor is a high-pitched inspiratory sound and indicates airflow turbulence in the upper airways. In the acute setting, stridor should prompt a review of causes such as epiglottitis or foreign body, and in chronic presentation conditions such as upper airway tumors, tracheal–bronchial stenosis, vocal cord dysfunction/paralysis, and airway narrowing due to thyroid enlargement should be excluded.
The diagnosis of asthma is usually apparent from the medical history with symptoms of variable and intermittent airway obstruction and objective measurements of lung function and spirometry support the diagnostic process. Similarly, the clinical history provides relevant information regarding the relationship between symptoms and allergen exposure, but skin prick testing and serology may be useful in identifying specific allergic triggers of asthma. Radiologic examination of the thorax, blood tests, and body plethysmography are not routinely indicated, unless there is some uncertainty in the diagnosis, where these tests may be used to exclude other conditions that may mimic asthma or complicate its clinical presentation.
Peak flow meters are portable devices, readily available for patient use, that measure the peak expiratory flow (PEF). Serial readings of PEF that vary by more than 20% either spontaneously or in response to treatment are supportive of a diagnosis of asthma. Twice-daily PEF measurements, morning and evening, may also demonstrate diurnal variation, which is a typical feature of asthmatic patients.
Spirometry measures the expiratory volume and flow of air using forced maneuvers from full lung inflation, as a function of time. Simple spirometry is important for objectively demonstrating airflow obstruction, confirming the diagnosis of asthma, establishing the severity of the disease, and monitoring the response to therapy. Patients with asthma typically show a reduced forced expiratory flow in 1 second (FEV1), reduced PEF, preserved forced vital capacity (FVC), and an FEV1/FVC ratio of 0.7 or greater, but with worsening disease, FEV1 less than 60% predicted the FEV1/FVC ratio is more usually <0.7.21 Home PEF monitoring may be of diagnostic use, confirming the diurnal variations in airflow obstruction, especially in patients who demonstrate normal spirometry during clinic visits. Spirometry also allows the assessment of the flow–volume loop, which shows a reduced maximum expiratory flow.
Bronchodilator reversibility is a measure of the magnitude of airway smooth muscle relaxation. A postbronchodilator increase in FEV1 of >12% and 200 mL is often considered evidence of reversible airway obstruction, where measures are taken 15 minutes after an inhaled short-acting β2-agonist (SABA). However, this level of increase is arbitrary and lacks sensitivity or specificity for detecting asthma. In addition, bronchodilator reversibility is diminished in well-controlled asthmatic patients, so it is not a good measure of asthma severity or response to therapy. In some patients, bronchodilator reversibility may be demonstrated by a 2- to 4-week trial of oral corticosteroids (prednisone or prednisolone 30–40 mg daily). Bronchodilator reversibility may also occur in patients with chronic obstructive pulmonary disease (COPD), and although asthma and COPD are distinct diseases, an “overlap syndrome” is described between the two conditions.22–24
Whole-body plethysmography is rarely required to establish a diagnosis of asthma in family practice, but may help in patients where there is diagnostic uncertainty. In stable asthma, measurement of the lung volumes may reveal an increase in residual volume, which reflects airway closure at a lung volume that is higher than normal. Air trapping is typically seen in patients with severe asthma. Airway resistance is characteristically increased and, during acute episodes of disease exacerbation, functional residual capacity and total lung capacity may also be observed to be increased. Measurement of the diffusing capacity of the lung (DLCO) may also differentiate patients with COPD from those with asthma. In stable asthma, DLCO is usually normal, but there may be a small increase in some patients. In contrast, patients with COPD typically have a reduced DLCO, which reflects alveolar septal destruction and loss of pulmonary capillary volume—characteristic features of emphysematous patients.
Bronchial Challenge Testing
Assessing bronchial hyperresponsiveness (BHR) is a sensitive tool that, although not routinely undertaken in clinical practice, may be helpful in diagnosing asthma, particularly when there is diagnostic uncertainty in the context of normal pulmonary function tests and unexplained chest symptoms (see Chapter 33).25 Bronchial challenge tests assess the abnormally increased airway hyperresponsiveness observed in patients with asthma, by detecting the exaggerated response to inhaled bronchoprovocative agents. The provocation agents can be classified into two categories: direct and indirect. Direct stimuli such as histamine and methacholine, which are normally used in the clinic, act on airway smooth muscle receptors, whereas indirect stimuli act through intermediate pathways that include the release of mast cell mediators, and/or through local and central neurologic reflexes. Indirect stimuli include adenosine monophosphate (AMP), mannitol, exercise, hypertonic saline, and isocapnic hyperventilation.
Increased BHR is typically defined as the inhaled concentration of the bronchoprovocative agent that reduces FEV1 by 20% (PC20). This criterion for the test has maximal sensitivity but not maximal specificity and thus, when a diagnostic PC20 threshold of ≤8 mg/mL is used, pharmacologic challenges are sensitive tests with a high negative predictive value, that is, a PC20 >8 mg/mL excludes a diagnosis of asthma with a high degree of accuracy. Similarly, a positive result, although consistent with is not diagnostic for asthma. False-negative results can be obtained in patients who experience only intermittent symptoms and are tested when they are asymptomatic. The prevalence of abnormal responsiveness in nonatopic, non-asthmatic subjects who have no history of prior respiratory problems ranges between 5% and 10%. Knowledge of family history, personal atopy, and comorbidities clearly improves the prediction that abnormal airway responsiveness predisposes to the subsequent development of asthma.26
Technical factors related to the test procedure must be strictly controlled and follow standard operating procedures that include: the aerosol generation, the method of inhalation (intermittent versus continuous), and the measurement and calculation of the response. Medications such as β2-agonists, theophylline, long-acting muscarinic antagonists, and corticosteroids (CSs) may influence the test and decrease airway responsiveness. Measuring BHR may have additional utility in the management of asthma. Patients whose disease is considered to be clinically controlled, may still have BHR and underlying airway inflammation and studies have shown that using AHR to guide treatment with inhaled corticosteroids (ICSs), leads to an additional improvement in symptoms, lung function, and airway biopsy findings, compared with conventional assessment.27
Exercise testing of patients using cycle, treadmill, or free running challenges is occasionally undertaken to show post-exercise bronchoconstriction if there is a suggestive history of exercise-induced asthma.28 In professional athletes, asthma may be both under- or overdiagnosed and objective confirmation by appropriate lung function testing with bronchodilator or exercise challenge is often needed. Allergen challenge is rarely utilized in the routine management of patients with asthma and should only be undertaken by a specialist center if a specific causative or occupational agent is to be identified, such as aspirin.
Blood tests are usually not helpful in establishing the diagnosis of asthma. The eosinophil count in the peripheral blood film may be raised in atopic conditions and eosinophilia may support a diagnosis of asthma; however, a normal level does not rule out atopy or exclude asthma. In patients receiving CSs, eosinophilic counts may be normal or low. Because of their poor sensitivity and specificity, blood eosinophil counts are not recommended in the routine monitoring of asthma severity or as a barometer of airway inflammation. Markedly high levels may be present in disorders such as tropical parasitic eosinophilia, allergic bronchopulmonary aspergillosis (ABPA), Churg–Strauss syndrome, and Loeffler's syndrome as discussed elsewhere in this volume. In these hypereosinophilic conditions, clinical suspicion may warrant additional blood tests directed to ruling out vasculitis or ABPA, which are uncommon causes of asthma symptoms. Recently, blood eosinophils counts have been found to be useful in predicting which patients with severe asthma respond best to anti-IL-5 therapy.29
Total serum immunoglobulin E (IgE) may be measured in patients. Epidemiologic studies demonstrate an association between asthma and total serum IgE levels, standardized for sex and age. There is also a relationship between total serum IgE and asthma in patients with negative skin tests. Importantly, total IgE levels are used to calculate the dose of the anti-IgE antibody therapy, omalizumab, when it is used for asthma treatment as discussed below in Anti-IgE Monoclonal Antibodies. Blood tests of specific IgE to inhaled allergens, radio-allergosorbent testing (RAST), and ImmunoCAP may help identify or confirm allergy to specific allergens, such as house dust mite, cockroach, Aspergillus species, pollens, or animal dander.
In acute exacerbations of disease, arterial blood gases may reveal hypoxemia and the arterial PaCO2 may be reduced due to hyperventilation. With a severe exacerbation, the arterial PaCO2 may rise due to respiratory muscle fatigue and an inability to maintain the required alveolar ventilation.
If the clinical history suggests specific aeroallergens are important triggers or when asthma symptoms in a patient are accompanied by other symptoms typical of allergic disease, such as conjunctivitis or rhinitis, skin prick tests may be helpful to determine whether the patient is allergic, and to investigate the role of specific allergens as a cause of asthma. Sensitivity to a particular allergen such as house dust mite, cockroach, Aspergillus species or animal dander can be verified by skin tests or in vitro serum antibody studies (see above). Antihistamines and antidepressants should be avoided when undertaking testing as these drugs can interfere with the response. Positive responses on skin prick testing may help encourage patients to undertake allergen avoidance measures or, in selected cases, may help develop immunotherapy regimens.
Chest radiography is usually unremarkable and normal in patients with mild-to-moderate asthma; however, in more severe disease, nonspecific findings such as hyperinflation, prominent hilar vessels, and bronchial wall thickening may be seen. In patients with an exacerbation of their symptoms, chest radiography may be useful to exclude a pneumothorax. Consolidation shadowing in the lung usually indicates pneumonia or eosinophilic infiltrates in patients with ABPA. High-resolution computed tomography (HRCT) of the chest may identify atelectasis, bronchial wall thickening, or areas of bronchiectasis in patients with severe asthma, but these changes are not diagnostic of asthma. Emphysema is absent. Multidetector computed tomography (MDCT) undertaken in inspiration and expiration provides additional information concerning the tracheobronchial tree during the entire respiratory cycle.
The measurement of fractional nitric oxide gas in the exhaled breath (FeNO) of patients is being utilized as a noninvasive test to assess intrapulmonary eosinophilic inflammation.30 Portable, compact hand-held devices allow FeNO measurements to be undertaken at the bedside and in family practice. Typically, asthmatic patients have elevated FeNO levels compared with healthy subjects, which correlate with the amount of eosinophils in sputum. ICSs and oral leukotriene receptor antagonists have been shown to decrease FeNO levels. These observations suggest a possible role for FeNO as an index of asthma disease severity, as a test of treatment efficacy and, in the assessment of patient adherence with asthma therapy. Measurements of FeNO have also been used successfully to titrate inhaled steroids without any loss of asthma control; thus, FeNO may be used as a tool in conjunction with other clinical measures to optimize asthma management as recommended by guidelines, that is, achieving disease control using the lowest doses of medications possible. In the research environment, FeNO can be partitioned into that arising from the central bronchial/conducting airways, or to that generated in peripheral alveolar regions, allowing an assessment of the site of intrapulmonary inflammation.31,32 Patients with severe refractory asthma have shown greater alveolar NO concentrations compared to those with mild asthma. Increased FeNO may be a good predictor of which patients respond best to anti-IL-4/13 therapy since IL-4Rα activation causes the release of NO from airway epithelial cells.33
The sputum differential count may be helpful. Induced sputum eosinophil counts have been used as an endpoint in clinical trials of therapeutic agents targeted at patients with eosinophilic lung diseases like asthma.34 Research studies have shown sputum eosinophilia predicts clinical outcomes, particularly asthma exacerbations, when CSs are withdrawn. Induced sputum eosinophil counts have also been shown to guide anti-inflammatory treatment in patients with asthma in a management strategy that minimizes eosinophilic inflammation.27 However, induced sputum remains a research tool as it is rather an unpleasant procedure for the patient and further studies are needed before measurement of sputum eosinophils can be widely used as a biomarker to monitor patients in clinical practice.
There are a number of conditions to consider in the differential diagnosis of asthma and these are listed in Table 46-3. Usually, it is not difficult to differentiate asthma from other conditions causing wheeze and dyspnea. The degree of diagnostic accuracy is probably dependent on the age of the patient, where the diagnosis in young adults is usually not difficult since there are few other conditions that mimic asthma or confound its clinical presentation. With increasing age, cardiovascular disease and other forms of chronic lung disease are more common, and the differential diagnosis of episodic chest symptoms is broader.
Table 46-3Differential Diagnosis of Asthma ||Download (.pdf) Table 46-3 Differential Diagnosis of Asthma
|Upper Airway ||Pulmonary ||Cardiac ||Other |
|Foreign body ||Allergic bronchopulmonary aspergillosis (ABPA) ||Angina ||Anemia |
|Postnasal drip ||Bronchiectasis ||Left ventricular failure ||Carcinoid |
|Upper airway obstruction ||Churg–Strauss syndrome ||Mitral valve disease ||Functional |
|Vocal cord dysfunction ||COPD || ||Gastroesophageal reflux |
|Tracheobroncho-malacia ||Cystic fibrosis |
Interstitial lung disease
| ||Hyperventilation |
Patients with upper airway obstruction can mimic severe asthma, and typically these patients present with localized wheeze and stridor of the large airways. Assessing the flow–volume loop in such patients will reveal a reduction in inspiratory flow as well as expiratory flow, and bronchoscopy can demonstrate the site of narrowing in the upper airways. Vocal cord dysfunction can be assessed using nasoendoscopy, which allows the observation of abnormalities in the movement of the vocal cords, and is most helpful when adduction of the cords is detected in the presence of the patient's symptoms.35 Persistent wheezing auscultated in a localized area of the chest wall may indicate endobronchial obstruction due to lung cancer or a foreign body. Eosinophilic pneumonias and systemic vasculitis, including the Churg–Strauss syndrome and polyarteritis nodosa may be associated with wheezing and their systemic clinical manifestations may help in their identification.
COPD is usually easy to differentiate from asthma. The symptoms in patients with COPD are more persistent, show less variability, are progressive, and usually exhibit minimal reversibility to bronchodilator agents. The literature highlights an “overlap syndrome,” where COPD patients have features of asthma with increased sputum eosinophils and a response to oral corticosteroids; these patients probably have both diseases concomitantly.24 Important cardiologic causes to consider include left ventricular failure, where usually bibasilar lung crackles are present in contrast to the scattered polyphonic wheeze in asthma. Anemia should always be thought of as a cause of dyspnea, especially in elderly patients. The symptoms of gastroesophageal reflux disease (GERD) may be mistaken for those of asthma; however, it is important to recognize that GERD is common in patients with asthma and has been identified as a potential trigger for asthma symptoms.36
Treating asthmatic patients is generally straightforward; with effective and safe drugs, most asthmatics are now managed by family doctors. The successful management of asthma requires an appreciation of the heterogeneity of the disease with respect to etiology, clinical presentation, severity, natural history, and response to therapy. It is unlikely that a single management approach will work for all patients and hence, treatment should be tailored to the individual patient. It will also be recognized that symptom severity in patients varies over time with periods of remission that are interspersed with acute exacerbations, and thus the patient should be monitored regularly and treatment should be modified on an ongoing basis to meet the patient's current needs. There are several aims in the management of patients with asthma (Table 46-4) and although prominence has been placed on drug therapy, there are important patient-orientated approaches that focus on correct inhaler usage, emphasize self-management action plans, and address environmental control.
Table 46-4Aims of Asthma Therapy ||Download (.pdf) Table 46-4 Aims of Asthma Therapy
|Control symptoms |
|Prevent (or minimize risk of) exacerbations |
|Eliminate emergency visits |
|Maintain lung function as close to as normal levels as possible |
|Decrease diurnal variation, especially nocturnal |
|Maintain normal levels of daily activities, including exercise |
|Eliminate or minimize adverse effects from medicine |
Drug delivery to the lungs via the inhaled route remains the cornerstone of therapy for patients with asthma. Inhaled therapy targets drug directly to the lungs and allows a distinct therapeutic advantage over systemic therapy with the use of smaller drug doses, a more rapid onset of therapeutic action, and decreased adverse effects. There are several types of inhaler device and drug delivery systems used in clinical practice for the management of asthma and these include the pressurized metered-dose inhaler (pMDI), spacers, dry powder inhalers (DPIs), and nebulizers.37 There are potentially over 250 device drug combinations available and this leads to confusion in prescribing among healthcare practitioners. Indeed, studies have shown that not just patients, but healthcare workers are uncertain about the correct use of inhaler devices and physician's knowledge, in particular, remains poor and may be related to a lack of education and instruction about inhaler usage during their training.38 It is confusing in the literature as there are 299 definitions of inhaler errors, but clearly it is recognised that a lack of knowledge and recognition with respect to the proper use and working of an inhaler might lead worsening health outcomes for the patient.39 It has been shown that training and counselling patients in their inhalation technique can increase their adherence to device usage, and patients may be assessed with respect to their suitability for a particular inhaler device by using portable handheld meters that assess inhalation flows. Evidence-based guidelines from the American College of Chest Physicians,40 recommend the following points for healthcare practitioners to consider when choosing an inhaler for their patient; the clinical condition and disease severity; availability of the inhaler device for the drug prescription; the patient's ability to use the selected device correctly; consideration given to using the same device type for all drugs; the setting and convenience of outpatient and inpatient use; the time required for drug administration; cost and reimbursement; and the inhaler preference of the patient as well as the prescriber. The advantages and disadvantage of the common inhaler device types are shown in Table 46-5.
Table 46-5Advantages and Disadvantages of Inhalation Devices ||Download (.pdf) Table 46-5 Advantages and Disadvantages of Inhalation Devices
| ||Advantages ||Disadvantages |
| Pressurized metered-dose inhaler (pMDI) ||Compact and portable ||High oropharyngeal deposition |
| ||Multi-dose ||Difficulty in hand–mouth coordination |
| ||Quick treatment time ||Propellants may cause “cold Freon” effect and affect climate change |
| ||Drug in sealed canister ||Difficult to assess empty canister |
| ||Inexpensive || |
| Dry powder inhaler (DPI) ||Compact and portable ||Need adequate inhalation flow to disperse drug |
| ||Quick treatment time ||High oropharyngeal deposition |
| ||Breath-actuated function removes need for coordination ||Humidity can cause drug degradation |
| || ||Patients may be intolerant to additives, e.g., lactose |
| Nebulizers ||Large doses of drug can be given ||Bulky, cumbersome, and expensive |
| ||Can be used with relaxed tidal breathing ||Wasted drug in nebulizer reservoir |
| ||Suitable for young, old, and acutely ill patients ||Variation in aerosol output performance between models |
| ||Many drug solutions can be aerosolized ||Time consuming |
| || ||Need for power source |
| || ||Regular cleaning and maintenance |
Pressurized Metered-Dose Inhalers
The pMDIs contain the drug as a liquid suspension or solution with propellant in a sealed canister and, other formulation ingredients may be present such as ethanol, chemical preservatives, flavoring agents, and surfactant. Most inhaler therapies are now free of chlorofluorocarbon (CFC) propellants having being replaced by non–ozone-depleting propellants such as hydrofluorocarbons (HFCs). Upon actuation of the pMDI canister, there is quick vaporization of the propellant and this provides the force to aerosolize and propel the liquid drug out of the canister at high velocity. Vaporization of the propellant also causes cooling of the drug aerosol which can sometimes give rise to the “cold Freon effect,” which is the sensation experienced by some patients of cold aerosol hitting the back of their oropharynx, which can stop them from inhaling the drug and sometimes cause paradoxical bronchospasm. Some of the formulation ingredients added to pMDIs described above, have been shown to cause bronchospasm, wheeze, and cough in asthmatic patients. pMDIs are compact, portable, and inexpensive devices. Recent advances in the technologic design of pMDIs include the addition of a dose counter.
Optimal clinical efficacy with a pMDI is obtained when the device is actuated at the start of a deep and slow inhalation lasting for 5 seconds followed, at the end of inspiration, by a breath-hold pause of 10 seconds. Failure to inhale slowly and deeply with pMDIs is a more common mistake than the actual patient coordination between inhalation and actuation. However, the latter problem is more pertinent in elderly patients and add-on spacer attachments, device-holding adaptors, and breath-actuated pMDIs have been developed to overcome this. Breath-actuated metered-dose inhalers utilize the patient's inspiratory force to trigger and activate the inhaler device, although it has been shown breath-actuated pMDIs offer no advantage over patients with good conventional pMDI inhaler technique. In contrast, breath- “coordinated” devices are different from breath-“actuated” metered-dose inhalers in that they do not depend upon the patient's inspiratory flow for actuation and help patients achieve coordination with aerosol inhalation.
Spacer devices are used with pMDIs and are designed to assist in the delivery of inhaled drug to the lungs by promoting ease of pMDI use, and reduce oropharyngeal deposition by slowing the high velocity of the emitted aerosol cloud. The plastic walls of the spacer trap the large dug particles and this decreases oropharyngeal impaction, which may lead to a decrease in local unwanted side effects, particularly with CSs, and also a reduction in systemic adverse effects by minimizing the amount of drug absorbed via the gastrointestinal tract. In addition, increasing the distance the aerosolized drug travels (by using the spacer as an extension attachment to the pMDI device), slows the emitted aerosol cloud and allows more evaporation of the propellant, leading to relatively smaller drug particles that have a greater potential to deposit within the lungs. Spacers include valve-holding reservoir chambers with a one-way inhalation valve in the mouthpiece only allowing airflow through the chamber when the patient inhales; simple extension devices that are non-valved add-on products that require a reasonably good amount of coordination; and reverse-flow devices where the aerosol spray is actuated away from the patient into a collapsible reservoir chamber or bag through which outside air is entrained to provide the airflow stream for inhalation.
Spacer devices each differ in their design characteristics and should be prescribed only with the pMDI they are compatible with, as each spacer–inhaler combination has distinct aerosol output characteristics.41 To reduce the electrostatic charge in spacers which can significantly contribute to decreased drug available to be delivered to the lungs, spacers should be primed with the pMDI prior to use, and one-dose actuation at a time from a pMDI into the spacer device should be employed as opposed to simultaneous multiple-dose administrations. Spacers should be washed with ionic detergent and air dried. Antistatic spacer devices are available and can be used.
DPIs are propellant-free devices that contain finely milled powdered drug particles bound into loose aggregates or, drug particles associated with larger carrier molecules such as lactose. DPI devices are breath-actuated in their operation, and critically rely on the patient's inspiratory effort to de-aggregate the drug from its carrier particle to achieve optimal delivery and deposition within the lungs. Studies have shown that DPIs are highly dependent on the patient's inspiratory flow for therapeutic success, and have observed that patients with asthma and those with COPD use suboptimal inspiratory flows from DPIs leading to low pulmonary deposition.42 In a large database study, insufficient inspiratory effort from DPIs was the most common inhaler error in this device class and associated with significant worsening of asthma and increased disease exacerbation.43
DPIs can be classified into single-dose delivery systems that either require drug to be individually loaded into the inhaler prior to use or where individual doses are dispensed from punctured gelatin capsules. In contrast, multiple-dosing delivery DPIs avoid the inconvenience associated with repeated drug loading and can be divided into “multi-dose” or “multi–unit-dose” systems. Multi-dose systems deliver drug that is metered from a powder reservoir, whereas multiple–unit-dose devices either contain drug sealed in individual foil blisters, or drug sealed in pockets on a moving strip. Deterioration of the drug may occur in damp and humid conditions, and so all these devices should be stored in a dry environment. A newer generation of DPIs have been developed that rely less on the patient's inspiratory effort, requiring either lower inhalation flows to aerosolize the drug or, in some circumstances, deliver the drug wholly independent of the patient's breathing maneuver.
The main types of nebulizer commonly used in clinical practice can be divided into two categories: ultrasonic and jet nebulizers.44 Ultrasonic nebulizers utilize the vibration from a piezoelectric crystal at a high frequency to produce aerosol clouds for inhalation from the liquid drug. Ultrasonic nebulizers are smaller and less noisy compared to jet nebulizers, but are usually less robust, more expensive, and not as effective in nebulizing liquid suspensions of drug. Jet nebulizers use either compressed gas or an electrical compressor to generate aerosolized particles. High-velocity air streams are generated and directed through a narrow Venturi opening, across the liquid drug solution/suspension, to produce aerosolized droplets within the nebulizing chamber.
Nebulizers require tidal breathing at rest for effective use and do not require much patient coordination. However, it is recognized that there is great variation in the aerosol output generated from each of the different nebulizer devices, and the inhalation maneuver will affect drug delivery to the lungs that can be greatly reduced with crying, as may occur with children, or when there are shallow and rapid inhalations.45 Consideration should be given to the nebulizer–facemask combination as incorrect mask insertion into the nebulizer may give rise to unwanted deposition of drug onto the face and eyes, particularly in children. Generally, nebulizer devices are large, lack portability, and have a longer treatment time than conventional inhalers.
There are now a newer generation of nebulizer devices that offer a marked improvement in the efficiency and precision of pulmonary drug delivery.46 These devices are more costly as units compared to conventional nebulizers, but may be cost-effective by decreasing drug loss from the nebulizer chamber particularly during exhalation, and overall by delivering a reduced drug dose to the lungs but more effectively. Nebulizer systems have also been developed that control the patient's inhalation maneuver so as to minimize the variability in dose delivery that occurs during use, and there are systems that provide feedback to the patient and allow an assessment of patient compliance.
A wide variety of agents are used in the management of asthma. Additional discussion can be found in Chapter 145, Pulmonary Pharmacotherapy.
Bronchodilators reverse the bronchoconstriction of asthma, principally by acting to relax airway smooth muscle, and this results in the rapid relief of symptoms. Bronchodilators are not adequate enough to control asthma in patients with persistent symptoms, as they have little effect on the underlying airway inflammation. The classes of bronchodilators in current clinical use include β2-adrenergic agonists, anticholinergics, and theophylline, where β2-agonists are the most efficacious.
Inhaled β2-adrenergic agonists are the drugs of choice for relief of respiratory symptoms due to acute airway obstruction.
β2-Agonists activate β2-adrenergic receptors resulting in an increase in intracellular cyclic AMP, which leads to relaxation of airway smooth muscle cells. β2-Agonists act as functional antagonists; that is, they prevent and reverse the contraction of airway smooth muscle cells by bronchoconstrictors, and it is this action that mainly accounts for their efficacy as bronchodilators in asthma. These drugs also have nonbronchodilator effects that include the inhibition of mast cell mediator release, the inhibition of sensory nerve activation, and a reduction in plasma exudation, which may be clinically useful.47
SABAs, such as albuterol and terbutaline, have a rapid onset of action and a 3- to 6-hour duration of activity. This pharmacodynamic characteristic of a rapid onset of bronchodilation allows these drugs to be used as quick-relief medications or “relievers” on an as-needed basis. As a matter of caution, increasing use of SABA indicates that asthma is not controlled and patients should be reviewed. At recommended doses, inhaled β-agonists have few adverse effects, although when used at higher doses by nebulizer, patients may experience short-lived side effect. Long-acting β2-agonists (LABAs) include formoterol and salmeterol. Both drugs are given twice daily by the inhaled route and have a duration of action of over 12 hours. In particular, formoterol has an onset of action as rapid as albuterol and can be used as a “reliever” component in fixed-dose combinations of LABA with ICS medication. LABA should not be used as monotherapy for the control of asthma of any severity and should not be given in the absence of ICS therapy as they do not control the underlying inflammation. However, fixed-dose combinations of LABA with ICS are now increasingly used in the management of asthma and have proved to be highly effective in improving the control of asthmatic patients, reducing disease exacerbations, and allowing asthma to be controlled using lower doses of CSs.48 Studies have also shown the clinical benefits of LABA/ICS fixed combinations compared with the monocomponents administered using two separate inhalers. Interestingly, the combination of formoterol and budesonide, and recently formoterol and beclomethasone dipropionate, have been demonstrated to be effective when used as both a controller and reliever agent (single maintenance and reliever therapy (SMART)) and thus provides the advantage of a single device used for both purposes.49
The commonest adverse effects of β2-agonists are palpitations and muscle tremors, which are unusual with the inhaled route and seen more commonly with high-dose nebulizer therapy and in elderly patients. The safety of β2-agonists has been an issue of concern. An association has been demonstrated between the amount of SABA used and asthma deaths, but thorough analyses demonstrate that the increased use of rescue SABA implies poor asthma control, which itself is a risk factor for asthma death. A slight increase in deaths from asthma has been observed with the use of LABA, but this is most likely related to the lack of use of parallel ICS, as the LABA therapy on its own fails to suppress the asthmatic airway inflammation, and this highlights the need to always use ICS when LABA are given which can most suitably be achieved by using a combination ICS/LABA inhaler.50 Patients should also be reminded to avoid β-adrenergic receptor–blocking drugs, including those contained in topical ophthalmic preparations, as they can precipitate severe and sometimes life-threatening asthmatic episodes. Accordingly, β-blockers are contraindicated during acute asthma exacerbations and the risk–benefit ratio should be considered before they are used in stable patients with asthma. Some patients experience deterioration in their asthma control following inhaled β-agonist treatment and possible mechanisms and contributory factors include paradoxical bronchospasm, increased BHR, and tolerance to the drug. With prolonged exposure to a drug, down-regulation of the β-receptor may occur and this can limit therapeutic efficacy; that is, lead to tachyphylaxis to treatment. Indeed, β-receptor mutations and gene polymorphisms have been implicated in influencing the response to inhaled β-agonists.51
Anticholinergic agents are another class of drugs to be considered in asthma management.
Muscarinic receptor antagonists, such as ipratropium bromide, induce airway smooth-muscle relaxation by blocking muscarinic receptors on airway smooth muscle, inhibiting vagally mediated cholinergic tone and preventing mucus secretion.47
In general, the anticholinergic drugs are not as efficacious in the acute relief of symptoms compared to the β2-agonists. Anticholinergics prevent the cholinergic reflex component of bronchoconstriction, whereas in contrast, β2-agonists inhibit all bronchoconstrictor mechanisms. Hence, anticholinergics tend only to be used as add-on bronchodilator treatment in asthmatics who remain uncontrolled on other inhaled therapy. In the treatment of acute severe asthma, high doses of anticholinergic therapy may be given by nebulizer, but should only be given following β2-agonist treatment as anticholinergics do not have such a fast onset of bronchodilation. A combination preparation of albuterol and ipratropium bromide is available for nebulization therapy. Tiotropium is a muscarinic antagonist that has been used in the management of patients with COPD, and is currently the only long-acting muscarinic antagonist that has been licensed for use in asthmatic patients with poorly controlled asthma in Steps 4-5. Tiotropium has a higher selectivity for antagonism of M3 receptors and it also dissociates more slowly, which collectively lead to prolonged smooth muscle relaxation and long-acting bronchodilation.
Adverse effects are usually not a concern with anticholinergics as there is minimal absorption into the systemic circulation, but the most commonly experienced side effect is dry mouth, and in elderly patients, glaucoma and urinary retention can occur.
Oral theophylline was primarily used as an adjunct bronchodilator treatment, but due to its narrow therapeutic index and adverse effect profile, together with the availability of safer and more effective alternatives, theophylline is now infrequently used in patients with asthma.52
Theophylline inhibits phosphodiesterases in airway smooth muscle cells, which increases intracellular cyclic AMP and this leads to a bronchodilator effect. However, the doses required for bronchodilator activity commonly cause adverse effects, which are mainly a consequence of direct phosphodiesterase inhibition. Theophylline has been shown to exhibit anti-inflammatory effects, which are likely to arise through different molecular pathways; for example, theophylline has been shown to stimulate a key nuclear enzyme, histone deacetylase-2, which is an important intracellular mechanism for switching off inflammatory genes that have been activated.
Theophylline is normally administered as an oral slow-release formulation either once or twice a day, as this results in more steady plasma concentrations compared to standard theophylline tablets. In severe asthmatic patients, theophylline may be used as an add-on bronchodilator treatment, although plasma concentrations of 10 to 20 mg/L are typically needed, and these levels are usually associated with adverse effects. In contrast, the anti-inflammatory effects of theophylline seem to occur at plasma levels below the traditional therapeutic range of 10 to 20 mg/L, and at low doses, the drug is better tolerated. Low-dose theophylline has additive effects to ICS and is particularly helpful in severe asthmatic patients, where withdrawal of theophylline may result in clear worsening of asthma control. Intravenous aminophylline is now seldom used for the treatment of asthmatic patients, only very rarely in those with acute severe asthma exacerbations.
The adverse effects of theophylline are directly related to drug levels in the plasma and are infrequently observed at concentrations below 10 mg/L. The measurement of plasma theophylline may be useful in determining and guiding the correct clinical dose. Headaches, nausea, and vomiting are the commonest adverse effects, which arise from the inhibition of phosphodiesterase. Palpitations and diuresis may be troublesome, and with higher plasma concentrations, epileptic seizures, cardiac arrhythmias, and death may occur due to adenosine A1-receptor antagonism. Oral theophylline is well absorbed through the gastrointestinal route and is largely inactivated in the liver by the enzyme CYP450 and so, drugs that inhibit CYP450 activity such as allopurinol and erythromycin may increase plasma levels of theophylline with consequently, a greater potential for adverse effects.
Corticosteroids (CSs) are potent anti-inflammatory agents and when administered by the inhaled route are the most effective therapy available for treating and controlling asthma, and have greatly contributed to a reduction in asthma mortality in the Western world.53
CSs reduce the number and activation of inflammatory cells in the airways. The reduction in eosinophils, activated T lymphocytes, and surface mast cells in the airways contribute to the lessening in the airway hyperresponsiveness that is seen with CS therapy. There are several molecular mechanisms underlying the action of CS on airway inflammation and the main pathways center on the inhibition of transcription factors NF-?B and AP-1, which switch off the transcription of multiple activated genes encoding inflammatory proteins such as cytokines, chemokines, inflammatory enzymes, and adhesion molecules. Another key mechanism in the action of CS is the inhibition of the recruitment of histone deacetylase-2 to the inflammatory gene complex, which reverses the histone acetylation associated with increased gene transcription. CSs increase the expression of β2-receptors and this may contribute to the complementary clinical effects observed when CS are combined with LABA.54 Transcriptional activation is responsible for most of the endocrine and metabolic adverse effects of CS.
Clinical Use—Inhaled Corticosteroids
CSs are usually administered by the inhaled route for maintenance controller therapy in patients with asthma. ICS have been shown to prevent the symptoms of asthma, reduce severe exacerbations rates, improve lung function, and reduce airway hyperresponsiveness. Early and timely treatment with ICS appears to avert the irreversible changes in airway function that occur with chronic asthma. Patients with persistent asthma stabilized on ICS experience increased exacerbations when treatment is withdrawn, indicating that ICS suppress symptoms and inflammation, but do not cure the underlying disease. ICS are beneficial in treating asthmatic patients of any age and at any stage of disease severity. They are first-line therapy for patients with persistent asthma and are usually administered twice a day, although ICS may be effective given once a day in some patients with mild symptoms. The dose–response curve of ICS is relatively flat, meaning that higher doses are only incrementally better than low-to-medium doses. If low-to-medium doses of ICS do not control persistent asthma symptoms, it is usual practice now to add a LABA, preferably as a combination of the two drugs delivered from a single inhaler device.
Clinical Use—Systemic Corticosteroids
Oral CSs are reserved to treat acute exacerbations of asthma. Typically prednisolone or prednisone 30 to 45 mg is given once daily for 5 to 10 days and on finishing the course of treatment, no tapering of the dose is required. A few asthmatic patients (approximately 1%) with severe disease may require maintenance treatment with oral CS and in these patients it is important to determine the lowest dose necessary to maintain asthma control in light of the greater potential for adverse effects with higher doses. CSs may also be administered intravenously (methylprednisolone or hydrocortisone) for the treatment of acute severe asthma, although studies show oral CSs are as equally efficacious and easier to take. The use of biological therapies such as anti-IgE and anti-IL-5 reduces the requirement for oral CS in selected patients with very severe asthma, so all patients on maintenance oral CS should be considered for these therapies.
ICS may give rise to local oropharyngeal adverse effects such as oral candidiasis, dysphonia, and hoarseness, but these may be lessened with the use of a spacer device. There exist concerns about the systemic adverse effects of ICS from swallowing of the oropharyngeal dose and lung absorption, but these depend upon the individual pharmacokinetic properties of the different CS and overall, studies show that ICS have minimal systemic adverse effects.55 At higher drug doses, ICS may suppress plasma and urinary cortisol levels, and in pre-pubertal children it has been shown that the initial decrease in attained height from ICS persists as a reduction in adult height, but is not progressive or cumulative and is approximately a loss of 1 cm. Most importantly, ICS allow the effective control of asthma symptoms and disease, and maintenance therapy may decrease the need and number of prescribed courses of oral CS, and thus, reduce the total-body systemic exposure to CS in general.
Oral CS gives rise to greater systemic adverse effects than ICS, with a greater potential in those on chronic maintenance therapy. Adverse effects include bruising, diabetes, truncal obesity, osteoporosis, duodenal and gastric ulceration, hypertension, mood and behavioural changes, proximal myopathy, and cataracts. It is important to assess and monitor bone density if patients are administered chronic oral CS therapy so that preventive treatment for osteoporosis with bisphosphonates or estrogen in postmenopausal women may be initiated if levels of bone density are borderline or low. If CS adverse effects are a considerable problem, steroid-sparing agents may occasionally be considered.
Leukotriene pathway inhibitors are a group of compounds that alter the pathophysiologic effects of leukotrienes derived from the 5-lipoxygenation of arachidonic acid. Two classes of agents are available: inhibitors of the 5-lipoxygenase enzyme (zileuton) and cysteinyl-leukotriene receptor type-1 antagonists (montelukast, zafirlukast, and pranlukast).56
Cysteinyl-leukotriene receptor type-1 antagonists inhibit the smooth muscle bronchoconstriction, microvascular leakage, and eosinophilic airway inflammation that occur through activation of cys-LT1-receptors. These agents predominantly act on the inflammatory mediators produced by mast cells in asthma, and also to a lesser extent on mediators produced by eosinophils.
Antileukotrienes have less effect on airway inflammation and provide modest clinical benefit compared to ICS. ICSs are more effective anti-inflammatory agents and clinically superior in controlling asthma than antileukotrienes. Antileukotriene treatments may be useful as add-on therapy to selected mild asthmatic patients on low-dose ICS, although these agents are less efficacious than add-on therapy with LABA. Antileukotrienes may be helpful when CS use is poorly tolerated or not desired by the patient, or there is concomitant rhinosinusitis. These drugs are usually given orally once or twice a day.
Antileukotrienes are usually well tolerated, but can sometimes give rise to gastrointestinal upset, hepatotoxicity, and hypersensitivity reactions including anaphylaxis and angioedema.
Cromolyn sodium and nedocromil sodium are classified as asthma-controller drugs. Their main mechanisms of action seem to be to inhibit sensory nerve and mast cell activation, and therefore they are effective in blocking trigger-induced asthma such as allergen- or exercise-induced symptoms. However, these drugs have a short duration of action, requiring up to four times a day inhalation, and consequently have somewhat little benefit in the long-term control of asthma. They are popular in the treatment of children with asthma because they are remarkably safe, although they are inferior to ICS with respect to most relevant clinical outcomes, and low-dose ICSs are now favored in children as they are more efficacious and have an established safety profile.
Some patients experience serious adverse effects with CS therapy, especially oral CS therapy in those with severe asthma, and in an attempt to minimize CS exposure and reduce patient requirement, various immunomodulatory treatments have been tried. Many agents have been utilized as steroid-sparing therapies including azathioprine, colchicine, cyclosporin A, gold, methotrexate, and intravenous gamma globulin; but none of these treatments have shown long-term efficacy and importantly, each has been associated with a high-risk adverse effect profile and cannot be recommended to be used in lieu of CSs.
Anti-IgE Monoclonal Antibodies
Omalizumab is a monoclonal antibody to IgE that inhibits IgE-mediated reactions by neutralizing serum IgE without binding to cell-bound IgE. It is used as an adjunctive agent for atopic asthmatic patients who are dependent on CS therapy.57 Studies in patients with moderate-to-severe CS-dependent asthma show an improvement in asthma control, a reduction in the number of disease exacerbations, and a significant steroid-sparing effect. However, anti-IgE treatment is very expensive and appropriate only for specific patients who have a high circulating IgE within a precise range and are not controlled on maximal doses of inhaled and/or oral CS therapy. Omalizumab is usually given as a subcutaneous injection every 2 to 4 weeks and is relatively safe with few significant adverse effects, although anaphylaxis has occasionally been reported. A 3- to 4-month trial of therapy should be undertaken to ascertain any objective benefit with this treatment.
Despite maximal inhaled therapy and maintenance courses of OCS treatment, there are a small proportion of patients with asthma who are extremely difficult to control, and may be potential candidates for biological treatment of their disease. A number of immune system modulators have recently been licensed and approved for use in patients with severe asthma, and of these, the main biological therapies are inhibitors to target the key cytokines involved in the chronic airways inflammation of asthma.58 As the inflammation in patients with asthma is usually allergic with activation of mast cells and of eosinophils mainly orchestrated by Type 2 immunity, which involves T helper 2 (Th2) cells and type 2 innate lymphoid (ILC2) cells, IL-4, IL-5 and IL-13 have been key cytokines that have been targeted.58
There are currently three anti-IL-5 treatments approved for use in selected patients with severe Type 2 asthma; mepolizumab, reslizumab, benralizumab.
Mepolizumab is a blocking antibody to IL-5 administered by subcutaneous injection every 4 weeks, and initial studies in unselected patients and those with milder disease were unconvincing in their benefit to patients. However, recent clinical trials in severe asthma patients with specific inclusion criteria including ongoing respiratory symptoms, frequent disease exacerbations, and increased sputum eosinophils (greater than 3%) showed a reduction in both disease exacerbations and the maintenance dose of OCS.59 However, there was only little improvement in respiratory symptoms, pulmonary function and quality of life and hence ongoing inhaled maintenance therapy with ICS/LABA may still be needed.
Reslizumab is also a blocking antibody to IL-5 administered intravenously every 4 weeks, which is a potential drawback compared to the other treatments that has shown similar benefit to mepolizumab; again, the clinical effectiveness is dependent on eosinophil counts (blood eosinophils ? 400 per microliter).60 Higher doses of reslizumab than mepolizumab can be administered so it may be considered in those patients who do not show a good response to mepolizumab.
Benralizumab is an antibody to IL-5 receptor (IL-5Rα) receptor administered subcutaneously every 4-8 weeks, and has been shown not only to benefit patients with severe asthma but also those with milder disease.61 In patients presenting with an acute asthma attack, benralizumab administered as a single dose led to decreased disease exacerbations in the following 12 weeks post-exacerbation, particularly in those patients that were hospitalized because of their acute exacerbation.62 Benralizumab induces death of eosinophils and it rapidly clears eosinophils in the airways and may have a more rapid onset of action than antibodies that target the cytokine. Increased blood eosinophils counts predict a better response; therefore, only patients with blood eosinophil counts of over 300/?l should be considered for this expensive therapy.
Anti-IL-4, Anti-IL-13 treatments
IL-4 and IL-13 signal through a common receptor IL-4Rα, and both cytokines promote eosinophilic airways inflammation. In adult patients with asthma, IL-4 expression is low and poor outcomes in preliminary clinical studies directed attention to blocking IL-13 directly.58 However, lebrikizumab, an antibody specifically blocking IL-13, showed marginal benefit in two recent clinical trials and has not been pursued for clinical approval.63 Similarly, tralokinumab, also an IL-13 blocking antibody, performed poorly in recent clinical trials with minor changes in lung function, asthma control, and exacerbation outcome measures in patients with severe uncontrolled asthma.64 In contrast, the clinical trials with dupilumab, an antibody against IL-4Rα, have shown much better clinical benefit than those with the IL-13 antibodies. Dupilumab administered subcutaneously every 4 weeks, has been shown to improve symptoms, lung function, and markedly reduce asthma exacerbations in moderate-severe asthma patients poorly controlled on maximal inhalation treatments, where interestingly FeNO was a good biomarker of response, but baseline blood eosinophil counts were not.65 It is also licensed for use in patients with severe eczema and is effective in the treatment of rhinosinusitis and severe nasal polyposis.
Blocking upstream cytokines such as thymic stromal lymphopoietin (TSLP) which orchestrate type 2 inflammation may be more effective than targeting individual downstream cytokines. Tezepelumab, a blocking antibody to TSLP has been shown to be effective in inhibiting responses to inhaled allergen (early and late) and in reducing blood and sputum eosinophils, FeNO and IgE in patients with mild asthma.66 In patients with severe asthma, clear reductions in acute disease exacerbations and decreases in FeNO and blood eosinophil counts were observed.67
Other immunomodulating treatments
Currently, there are many drugs in development or in early human clinical trials in patients with subtypes of severe asthma targeting various aspects of the inflammatory pathways including those directed at cytokines (IL-25, Il-33, GM-CSF, IL-1, IL-6), transcription factors (GATA-3), neutrophils (TNF, IL-17), chemokines (CCR3, CXCR).58 Anti–TNF-α antibodies, although mechanistically promising, have not been shown to be effective in patients with severe asthma. New broad-spectrum anti-inflammatory treatments include phosphodiesterase-4, NF-?B, and p38 MAP kinase inhibitors, but these drugs act on signal transduction pathways that are common to many immune cells, and present the risk of troublesome adverse effects particularly by the parenteral route and hence, there is ongoing research into their delivery by the inhaled route.
It is clear from the clinical trials of biologics, and the current enriched interest and development of drugs targeting the immune pathways in asthma, that the appropriate selection of patients, identification of responders, and the development of biomarkers to monitor treatment response are critical in order to guide clinicians when considering the use of these highly expensive treatments. The effectiveness of anti-IL-5 treatments is highly dependent on the baseline blood eosinophil count, with greater clinical response in severe asthma patients with a blood eosinophil count ? 300 per microliter. In contrast, FeNO rather than blood eosinophils is a good predictor of response to anti-IL-4/13 treatments, and for anti-TSLP treatment, effectiveness did not depend upon raised blood eosinophil counts or FeNO.
It has also been recognized that existing specialist clinic resources must be directed at addressing non-adherence to inhaled therapy, as biological interventions could end up becoming a very costly and expensive alternative to rectify non-adherence.68 Most studies have been short term for 12 months and the long term safety profile of these agents particularly on the body's immune defense system against infections is largely unknown, although as licensed treatments are now being used this data will be monitored in post marketing surveillance.
Allergen immunotherapy is of benefit in highly selected patients with defined allergic triggers.69 Asthmatic patients with a single specific allergic trigger and concomitant nasal symptoms derive the greatest benefit than patients with multiple allergic triggers. Allergen-specific immunotherapy (ASIT) involves the repeated administration of allergen products to induce immunologic and clinical tolerance to the specific allergen. ASIT may be given subcutaneously and studies have supported efficacy by this route of administration, but there is a risk of adverse effects including anaphylaxis. In contrast, sublingual ASIT has recently been shown to be an effective and safe alternative in patients with seasonal allergy, and clinical studies with house dust mite allergic asthma are underway.
Alternative therapies may be popular and more acceptable with some patients and include acupuncture, breathing control, chiropraxy, homeopathy, hypnotherapy, and yoga; but placebo-controlled studies show these treatments lack efficacy and they should not be clinically recommended.70 The concern with these therapies is that they may lead to discontinuation of effective drug therapy and destabilize asthma control in patients. However, as these therapies are considered not to be harmful, patients may utilize them as an adjunct to their conventional pharmacotherapy.
Bronchial thermoplasty (BT) is an endobronchial intervention for the treatment of adult patients with severe persistent asthma who remain uncontrolled with ICS and LABA. BT delivers controlled radio-frequency energy to heat the airway walls and reduces airway smooth muscle mass. Three randomized controlled clinical trials of BT versus usual care or sham intervention in patients with severe asthma have supported its effectiveness and safety; the Asthma Intervention Research (AIR) trial,71 and the Research in Severe Asthma (RISA) trial,72 which both compared BT to usual care, and the AIR2 trial,73 that compared BT with sham intervention. The AIR2 trial observed a significant reduction in severe exacerbations of asthma, decreased emergency room visits, improved asthma quality of life questionnaire (AQLQ) scores and less patient hospitalizations. These improvements persisted through 5?years of follow-up.74 Patients in the trials undergoing BT did report a transient increase in symptoms related to their asthma and, during the treatment phase, and increase in hospital admissions. Recently, an interim analysis of the 3-year follow-up results of BT in a post-marketing surveillance study mandated by the FDA (PAS2, Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma), confirmed findings observed from the AIR2 follow-up, with significant decreases in the percentage of patients with severe exacerbations (45%), emergency room visits (55%) and hospitalizations (40%).75
Although current asthma therapy with CSs and β2-agonists are effective in controlling disease symptoms in the majority of patients, poorly controlled asthma still remains a problem in a considerable proportion of patients.76 Poor adherence to prescribed controller therapy contributes to poor asthma control, and the use of combination LABA/ICS therapy delivered by a single inhaler device and/or the use of combination LABA/ICS therapy as both a controller and reliever agent, may partly address this problem. Ultra–long-acting bronchodilators with once-daily dosing have been approved for COPD but not for asthma, and these treatments have allowed the production of several combination therapies incorporated with once-daily CS are in development. Indeed, the majority of current inhaler devices target their treatment to the large airways of the lung and research is ongoing to assess the clinical implications of targeting inhaled therapy to the peripheral lung regions, where they may be ongoing untreated inflammation additionally contributing to the patient's clinical state.77 Asthma continues to remain an unmet need as the life-long treatments currently used only address the clinical symptoms and have little effect on the underlying structural alterations associated with asthma. There is also pressing need for the development of novel therapies for patients who have side effects with systemic CSs.78
CS resistance is a particular problem in patients with severe asthma, and several molecular mechanisms have been elucidated that may lead to novel therapeutic approaches, including the reversal of this resistance by drugs such as theophylline and nortriptyline. Studies of the steroid-sparing effects of macrolide antibiotics in asthma management have yielded discordant results. Macrolides might benefit some patients with infection by atypical bacteria, but recent results are not encouraging, although there could be an effect in patients with predominant neutrophilic asthma.
Management of Chronic Asthma
Management guidelines in asthma now focus on the control of asthma symptoms using a stepwise approach to drug therapy.1 There has been a shift away from treatment based on disease severity with the realization that asthma does not necessarily remain in the same category permanently, but may change over months or years and that patients may move up or down in their asthma severity based on factors such as the presence of allergens, the incorrect/correct use of medications and treatments, and lack of adherence to the prescribed treatment regimen. If control at a particular step is not adequate, then treatment should be increased to the next level. The principles of therapy embody the fact that effective treatment should lead to better asthma control and allow the patient to move to a less severe category, and therefore for ongoing management of asthma, classification by level of control may be more relevant and useful. The aims of chronic therapy in asthma are highlighted in Table 46-2.
The Global Initiative for Asthma (GINA) stratifies patients into four categories of the level of asthma control; controlled (where therapy is maintained or stepped down); partly controlled (where consideration is given to stepping up therapy); uncontrolled (where treatment is stepped up until symptom control is achieved); and exacerbation (where patients are treated according to the exacerbation algorithms).1 The characteristics that contribute to determining the level of control involve an assessment of the following: daytime symptoms experienced in the last week; limitations in activities of daily living; nocturnal symptoms or awakenings the need for rescue reliever medication during the week; lung function; and the number of exacerbations (if any) in the last week and last year.
The stepwise approach to asthma management is a description of the levels of treatment required to achieve good asthma control.1 Some patients may experience acute worsening of asthma control, such as those with a concomitant upper respiratory tract infection, and may need to step up more than one step at a time.
For all asthma patients, a SABA delivered by a metered-dose inhaler gives relief of acute symptoms. Recent updates to global strategy documents for the management of asthma and some national country guidelines have now incorporate ICS treatment at Step 1, recognising the nature of asthma as chronic inflammatory disease and the need to control (and treat worsening) symptoms with ICS maintenance therapy.79 The increasing use of a reliever medication more than three times a week, or triggering of symptoms from exercise, provide an indication that controller therapy is needed. An important, but often overlooked part of asthma management relates to measures to control environmental triggers. Recognized triggers that worsen asthma control in the patient such as aeroallergens or occupational agents should be avoided, although this is not always possible. Patients with asthma may also have several triggers; therefore the impact of avoiding a single trigger will vary considerably between patients. However, complete removal from exposure to house dust mite has been shown to reduce asthma severity and airway hyperresponsiveness.
Guidelines recommend that influenza vaccination should be administered in adult asthmatics. However, where studies suggest it is unlikely to induce asthma exacerbations, there is no conclusive evidence regarding the efficacy of vaccination on influenza-related asthma complications or a reduction in exacerbations of asthma. Asthmatic patients, especially the elderly or those with comorbid conditions that increase the risk of death from influenza infection, should receive inactivated influenza vaccine if there are no other contraindications. The CDC recommends a single dose of Pneumovax for adults from 19 to 64 who have chronic illnesses, including asthma.
When patient symptoms are no longer intermittent, the addition of a long-term controller medication on a scheduled daily basis is recommended, and the treatment of choice for all patients is an ICS to alleviate the underlying airway inflammation. It is usual to start with a low-to-intermediate dose of ICS twice daily (e.g., 200 ?g beclomethasone dipropionate (BDP) or equivalent BID) and if symptoms are controlled after 3 months the dose should be stepped down. However, if symptoms persist and are not controlled, a LABA should be added as a fixed combination drug with an ICS delivered from a single inhaler device, as studies show a clinical advantage compared with the monocomponents administered using two separate inhalers. Indeed, low-dose ICS with LABA therapy has been shown to be as efficacious at high-dose ICS treatment.80 The dose of the ICS should be adjusted up or down accordingly to the need for rescue inhaler treatment and to the control of the patient symptoms. Alternative add-on therapies to ICS that can be considered include low doses of slow-release oral theophylline or an antileukotriene, but these are less effective than the LABA/ICS combination.
In patients with worsening symptoms, the addition of low-dose slow-release oral theophylline to high-dose LABA/ICS may be helpful. Recently, it has been shown that the addition of the inhaled long-acting anticholinergic tiotropium bromide to LABA/ICS treatment in patients with poorly controlled asthma, significantly decreases asthma exacerbations and improves bronchodilator lung function.81,82 In patients with severe asthma who fail to achieve symptom control, maintenance therapy with systemic oral CSs may be indicated, and there should always be an aim to titrate down to the lowest possible daily (or every other day) dose that maintains asthma control. Occasionally, anti-IgE therapy with omalizumab may be tried in patients who are CS dependent and continue to remain uncontrolled, but this treatment is only suitable for highly selected patients. Allergen-specific immunotherapy may be considered in this group; however, the risk of severe events including death is highest in patients with severe asthma. Biologocal therapy is also now indicated in a small proportion of patients.
Once asthma patients achieve stable symptoms and have stable peak flow readings, it is important to slowly decrease therapy to find the optimal dose to control symptoms. Indeed, asthma severity may fluctuate and improve with time, owing to improved disease management, changes in environmental exposure, or because of the natural history of the disease, and most asthma guidelines recommend a step-down approach once patients are controlled.1 Overtreatment of patients, particularly with ICS, can cause significant morbidity and adverse effects, especially in moderate-to-severe asthmatics. It may also be unnecessarily costly. Unfortunately, in such patients there is a tendency to maintain a static treatment regimen, even after symptoms are controlled and clinical stability is achieved. Studies have now supported the notion that stable asthmatic patients on high-dose ICS may be overtreated and that reductions in the inhaled dose can be achieved without significant increases in asthma exacerbations, visits to the family practitioner, or recourse to oral CS use.83 Indeed, recent studies show that an efficient inhaler device may achieve a successful step-down without worsening symptoms, disease exacerbations or hospitalizations.84 A gradual reduction in medications starting with the treatment with the greatest toxicity should be attempted once stability is achieved and sustained for several months, and symptoms should be monitored on a long-term basis using both objective lung function and subjective symptom measures. Most patients should be maintained on an ICS, and this treatment should not be stopped as this provides anti-inflammatory protection. In those asthmatic patients that needed admission to hospital and/or ventilatory support, a longer period of stability on maintenance therapy may be justified before consideration of a step-down treatment approach.
Management of Refractory Asthma
Most asthmatic patients are controlled with appropriate stepwise therapy, but approximately 5% of asthmatics are difficult to control, do not remain symptom free despite maximal inhaled therapy, and may require maintenance treatment with oral CSs. In this group of patients, a thorough investigation of factors aggravating or contributing to poor asthma control should be undertaken. It is important to check adherence with medication and inhaler technique, particularly if the patient's disease is unstable despite the maximal recommended dose of therapy. Nonadherence with medication remains an important factor for the poor control of asthma and may be particularly manifest with ICS, as patients may be concerned about adverse effects or describe lack of immediate clinical benefit from this treatment.68 Monitoring adherence to ICS therapy in the clinic is difficult as there are no useful plasma measurements that can be made, however in contrast, the measurement of plasma cortisol suppression and absolute plasma drug concentrations may be useful in monitoring adherence to oral CSs. Evidence suggests nonadherence may be commoner in those with psychosocial problems or depression and these conditions should be actively sought and addressed during the clinical assessment. A detailed review of factors such as exposure to environmental allergens, unidentified occupational agents, or drugs that worsen asthma control such as aspirin or β-blockers should also be undertaken. Asthma may coexist with a number of disorders that can affect lung function, and the successful management of asthma often requires treatment of these associated conditions that are thought to aggravate asthmatic symptoms. Rhinosinusitis and gastroesophageal reflux disease are the most common of the disorders associated with poorly controlled asthma.
The relationship between rhinosinusitis and asthma is well established as described in the “united airway disease hypothesis,” where treating the inflammation of allergic rhinitis in the upper airways has been shown to translate into improved asthma control.85,86 It has also been postulated that poor asthma control may arise as a result of the inability of current inhaler devices to target drug therapy to the ongoing inflammation in the peripheral lung regions, and possibly treatment of this lung compartment with targeted anti-inflammatory therapy may result in improved symptoms.77 In spite of the lack of data from meta-analyses which fail to show a consistent effect of anti-reflux therapy on asthma symptoms and lung function, many clinicians will assess and treat the possibility that gastroesophageal reflux disease may be aggravating asthma.87
As discussed earlier, patients with vocal cord dysfunction may present with wheeze and stridor and an escalation in asthma therapy. This disorder can be assessed using nasoendoscopy to observe abnormalities in the movement of the vocal cords, and if confirmed patients should be weaned off CSs. Speech therapy intervention may be helpful. Bronchoscopy or MDCT to exclude tracheobronchomalacia may be considered. A reconsideration of the potential differential diagnoses should be explored in the refractory asthmatic patient and this may require specialist referral (Table 46-3).
Patients who require high doses of oral CSs to maintain asthma control are referred to as CS-“dependent” asthmatics. In contrast, patients with complete CS-“resistant” asthma show a failure to respond to high-dose oral CS therapy, but this is very uncommon affecting less than 1 in 1000 patients. Several molecular mechanisms have been implicated in CS resistance and the impairment of their anti-inflammatory action, and this has led to the identification of new drug targets for future therapies.88 There is evidence that in asthmatic patients who smoke (approximately 20% of the population), smoking itself hinders the anti-inflammatory action of CSs leading to relative CS resistance with the need for higher drug doses to achieve asthma control. It is recognized that smoking asthmatics compared to nonsmoking asthmatics have a faster decline in lung function, more severe asthma, more frequent hospital admissions, and a higher risk of death. Smoking cessation should be strongly pursued in this group as this intervention has been shown to reduce CS resistance and improve lung function.
Some asthmatic patients have unstable disease with rapid variations in lung function that may lead to recurrent and severe attacks of asthma, despite appropriate treatment for the disease.89 These patients may be divided into type I brittle asthma, where there is a sustained pattern of chaotic peak flow variability on a daily basis or; type II brittle asthma, where asthma symptoms and lung function are well controlled, but there are abrupt and unpredictable falls in peak flow that may be catastrophic and result in sudden death. These patients are difficult to treat as they do not usually respond to maximal high-dose CS therapy but rely and need subcutaneous epinephrine injections. The assessment of treatment adherence and education on allergen avoidance is particularly important in these patients and they should wear an identification bracelet of their condition. The importance of carrying a portable epinephrine autoinjector at all times and being taught to self-administer this treatment should be a central part of their management.
Asthma Education and Monitoring
Asthma education and training is important as patients need to understand the disease, its management, how to use inhalers properly, adverse effects of treatment, and importantly when to use reliever and controller treatments. Education may improve adherence to treatment recommendations and also engage the patient in self-management strategies particularly in terms of recognizing their symptoms, identifying and avoiding asthma triggers, objectively measuring any deterioration in their asthma control, and treating exacerbations of asthma at their earliest stages by stepping up their therapy. Educating the patient in the self-administration of oral CSs and access to healthcare advice are also important elements in a management program, which are designed to reduce emergency hospitalizations and patient morbidity. Studies have shown that written personal patient action plans result in better asthma control, reduced emergency room visits and hospitalizations, and decreased morbidity in both adults and children. Written plans are particularly useful and recommended in patients with unstable disease who have frequent exacerbations. The additional provision of a program of educational sessions (one-to-one or in small groups) with a knowledgeable healthcare professional has been shown to be more effective than written materials alone. Like drug therapy, the educational program and the method and frequency of reinforcement should be tailored to the patient's individual needs. Patients should be reassured that with proper treatment, their symptoms and occasional exacerbations can be minimized, and in most cases a normal lifestyle and life expectancy can be anticipated.
Home monitoring of asthma symptoms and control is an important aspect of self-management programmers. PEF measurements allow patients to be monitored on a long-term basis with relative ease using hand-held, compact, portable devices. Asthma treatment guidelines recommend patients use PEF measurements not only to monitor the course of the disease, but also to dictate self-administered treatment regimens.1 Indeed, studies show improvements in measures of asthma control when peak flow measurements are used by patients (in relation to their personal best peak flow) to adjust medication usage. However, despite the advantages of written plans highlighted above, the US Centers for Disease Control and Prevention (CDC) analyzed asthma data from adults and children between 2001 and 2009 in a national health interview survey and showed that only one-third of patients with asthma reported being given a written asthma action plan, and just over two-thirds of patients had been taught the appropriate response to symptoms of an asthma attack.90 It should be recognized that not all patients are capable of comprehending and executing complicated treatment plans. There are also concerns that peak flow–guided self-management may lead to overtreatment with medication, and hence the potential for increased morbidity due to adverse effects. Similarly, patients with severe asthma in whom self-management plans are more readily recommended, may tend to use more oral CSs where it may be unclear whether the increased use is appropriate or medically warranted (although the increase in medication may be initially viewed as a potential benefit of peak flow monitoring). Action plans should be written using clear, simple language and individualized based on patients' understanding of their asthma, its severity, and their demonstrated ability to comply with instructions. Recent interest in the use of digital technology to help monitor inhaler use, test lung physiology remotely and link with home and work environmental data may help predict and alert patients to worsening asthma control, and studies to assess digital technologies are currently underway.91,92
Management of Acute Severe Asthma
Asthma is characterized by exacerbations of disease, which can lead to substantial morbidity, occasional mortality, and considerable medical and economic costs. Patients with asthma fear disease exacerbations as they can be life-threatening and exacerbation-prone patients seem to be at increased risk for attacks of near-fatal asthma. Analysis of asthma mortality data identifies that patients experience worsening symptoms and deterioration in asthma control of a period of several hours to several days, before the event.93 Indeed, life-threatening episodes can develop in any asthmatic patient, but particularly those patients with severe and poorly controlled disease; those who frequently access the emergency room; or patients who are hospitalized, are all recognized to be at high risk of life-threatening events. The importance of educating all patients with asthma should not be underestimated, as well as their carers, and in particular healthcare professional should identify and closely monitor such at-risk patients.
Patients with a moderate exacerbation of their disease notice a deterioration in their asthma control by an increase in daytime and nocturnal symptoms of cough, chest tightness, wheeze, and dyspnea, that do not respond to their usual maintenance therapy and require more reliever drug. A history of prodromal symptoms may be elicited that precede an asthma attack, such as itching under the chin, discomfort between the scapulae, or inexplicable fear (impending doom). A fall in home peak flow recordings also signify a worsening of asthma and the GINA guidelines classify exacerbations based on the peak flow into mild (PEF >80% predicted), moderate (PEF between >60% and 80% predicted), and acute severe (PEF between <60% predicted).1 Patients may become so breathless in acute severe exacerbations that they become exhausted, unable to talk freely in complete sentences, and show life-threatening features of confusion, agitation, and cyanosis. Clinical examination usually shows an increased respiratory rate, hyperinflation, and tachycardia. In acute severe asthma, pulsus paradoxus (the accentuated decrease in systolic blood pressure [>10 mm Hg] during inspiration), may be present. Life-threatening signs are a silent chest, bradycardia, and hypotension. Investigations will show a marked fall in PEF and spirometric values; hypoxemic saturations on air and arterial blood gases may reveal a low PaO2, and initially a low PaCO2 usually due to hyperventilation. In life-threatening situations the PEF will be <30% of predicted, oxygen saturation (SaO2) measured by pulse oximetry <92% and, arterial blood gases on air will show a PaO2 <60 mm Hg (8 kPa) and a rising PaCO2 will indicate impending respiratory failure and requires immediate monitoring and therapy. A chest radiograph is not routinely recommended in the absence of a suspected pneumothorax, pulmonary consolidation, failure to respond to treatment satisfactorily, or a requirement for ventilation.
The cornerstone of therapy for worsening asthma control requires the escalation of both ICSs and quick-relief inhaled β2-agonists.1 Exacerbations of asthma should never be treated by escalating bronchodilators alone and asthma fatalities usually result when patients fail to promptly seek medical attention. Studies have shown patients dying from asthma commonly self-medicate with escalating doses of reliever bronchodilator medication in the preceding days to an asthma attack. A short course of oral CS therapy for at least several days may be needed to control and prevent a mild–moderate exacerbation and tapering of the dose should be undertaken with close outpatient follow-up. Very mild or subacute exacerbations in asthmatics with mild persistent disease may be managed in some cases by escalating the dose of ICSs in cases in which patients are taking low-doseCS. In less severe exacerbations, patients who promptly respond to treatment in the emergency department may be discharged but close outpatient follow-up is essential.
In patients with an acute severe exacerbation presenting to the emergency department, oxygen at high concentrations and high flows should be given continuously by face mask to achieve oxygen saturations (SpO2) of between 94% and 98%. Hypoxemia is to be avoided at all costs, as patients die from hypoxemia in acute asthma and oxygen therapy is critical to prevent death in severe acute asthma, so continuous monitoring of oxygen saturation is needed until there is a meaningful response to treatment.
High doses of inhaled SABA given either by nebulizer (oxygen-driven) or via a pMDI with a spacer should be the first-line agents in acute asthma and be administered as early as possible. While generally well tolerated, occasionally nebulized bronchodilators cause arrhythmia and continuous electrocardiogram monitoring is required. In those patients in whom inhaled therapy cannot be used reliably, or in severely ill patients with impending respiratory failure, intravenous β2-agonists may be given. In patients not responding, nebulized anticholinergic treatment (ipratropium bromide) may be added as they provide additional bronchodilation. Systemic CSs should be given in adequate doses in all cases of acute severe asthma for at least 5 days or until recovery and should be tapered after this response over a 2-week period, particularly in cases of severe asthma exacerbations. In patients unable to take oral CSs, intravenous therapy (e.g., hydrocortisone) should be administered in the emergency department.
A single dose of intravenous magnesium sulfate for patients has been shown to be effective when added to inhaled β2-agonists. It is relatively well tolerated and can be considered in patients with acute severe asthma who have not had an initial good response to inhaled bronchodilator therapy, or in those with life-threatening features.
Patients should be referred to the intensive care unit for intubation and ventilation if they have acute severe or life-threatening asthma that is failing to respond to therapy indicated by: a deteriorating PEF, worsening hypoxemia, a normal or rising PaCO2, poor respiratory effort, and exhaustion or confusion. Intravenous aminophylline may be used, but the risks of toxicity are much greater than when inhaled β2-adrenergic agonists are used. Sedatives should never be given as they may depress ventilation, and antibiotics should not be routinely administered, unless there are clinical or radiologic signs of pneumonia.
Dr. Omar Usmani is a recipient of a UK National Institute for Health Research (NIHR) Career Development Fellowship.
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